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Vol 15: Gene set analysis methods: statistical models and methodological differences.This article is from Briefings in Bioinformatics, volume 15.AbstractMany methods of gene set analysis developed in recent years have been compared empirically in a number of comprehensive review articles. Although it is recognized that different methods tend to identify different gene sets as significant, no consensus has been worked out as to which method is preferable, as the recommendations are often contradictory. In this article, we want to group and compare different methods in terms of the methodological assumptions pertaining to definition of a sample and formulation of the actual null hypothesis. We discuss four models of statistical experiment explicitly or implicitly assumed by most if not all currently available methods of gene set analysis. We analyse validity of the models in the context of the actual biological experiment. Based on this, we recommend a group of methods that provide biologically interpretable results in statistically sound way. Finally, we demonstrate how correlated or low signal-to-noise data affects performance of different methods, observed in terms of the false-positive rate and power.